The primary goal of this project over the last 18 years has been to develop radiotracers that can be used clinically to measure cardiac sympathetic nerve status in the living human. To this end, our laboratory several successful sympathetic nerve markers, including radio-iodinated meta- iodobenzylguanidine (MIBG), (11C]-meta-hydroxyephedrine (HED), [11C]epinephrine (EPI), and [11C]phenylephrine (PHEN). All of these agents are avidly taken up into cardiac sympathetic nerves by the neuronal norepinephrine transporter (NET) and subsequently stored in vesicles by the vesicular monoamine transporter (VMAT). However, while the very rapid uptake of these agents provides high quality images of heart, it also makes tracer kinetic modeling problematic. A major goal of this proposal is to produce a new sympathetic nerve tracer that is more suitable for tracer kinetic analyses than any we have previously developed. Such a tracer would be extremely useful in monitoring patients undergoing therapies which seek to halt or reverse the neurodegenerative processes seen in diseases such as diabetic autonomic neuropathy and heart failure. Two distinct approaches will be investigated in the search for a new sympathetic tracer more suited to kinetic analysis. (1) slowing the neuronal uptake rate of HED, EPI, and PHEN with selective structural alterations known to reduce their affinity for NET and VMAT. Slowing the neuronal uptake rate of these agents may be all that is necessary to permit more rigorous kinetic analyses. (2) measuring NET density in a new way with a novel class of neuronal markers: NET transport substrates that are subsequently irreversibly trapped within the neuron. We have targeted [11C]-labeled analogs of the 'suicide' MAO inhibitors tranycypromine and phenelzine, which are also NET substrates, as a starting point to investigate this new strategy for measuring neuronal density. We aim to extend our work on polar derivatives of the high affinity NET inhibitor desipramine (DMI) as markers of neuronal NET density by [18F-labeling our most promising DMI analogs to better study their myocardial kinetics out to longer times. Finally, [11C]- and [18F]-labeled polar derivatives of the psychostimulant methcathinone will be synthesized as potential NET markers and their in vitro NET affinities determined as the cloned human NET transporter.